We are nearing completion of a project which demonstrates that chronic exposure of rhesus monkeys to marihuana smoke and to intravenous delta-9-THC induces persisting changes in EEG activity from precise deep regions of the brain. The present project is designed to conclusively determine if cannabis sativa derivatives do indeed induce brain damage and if they do, what is the hazardous dose level and exposure period? Two new methods will be used to answer questions with respect to dose levels (relevant to man): (1) a smoking procedure permitting accurate simulation of man's smoking pattern, and (2) radioimmune assay for accurate determination of plasma levels of various cannabis ingredients. To establish a complete dose response curve, data will be gathered from smoking monkeys (some with implanted depth electrodes and some intact) with respect to relevance of dose per exposure and total dose effect. Further, acute and chronic effects on brain function of certain cannabis derivatives and metabolites will also be determined by intravenous injection of the compounds into monkeys prepared with deep electrodes. The Department has an EMI Scanner for computer cranial tomography. Since some data collected thus far indicate alteration in shape and size of the ventricles as a result of exposure to canabis derivatives, scans will be done on a limited number of intact (without deep electrodes since there is some evidence that the implants can alter ventricles) monkeys exposed to cannabis derivatives. And finally, light and electron microscopic studies will be performed on the brains of all experimental monkeys in follow-up to the physiological studies. In addition to the EEGs that will be obtained in those experimental monkeys prepared with deep electrodes, evoked potential recordings will also be made by applying stimuli between two leads of a bipolar electrode implanted at one anatomic site while recordings are being obtained between the two leads of multipolar electrodes implanted at other sites.